Amino Strecker-cyanohydrin synthesis

Strecker-cyanohydrin synthesis the synthesis of amino acids from aldehydes, HCN and NH3 in the presence of an aqueous fluid. 

The most general methods for the syntheses of 1,2-difunctional molecules are based on the oxidation of carbon-carbon multiple bonds (p. 117) and the opening of oxiranes by hetero atoms (p. 123fl.). There exist, however, also a few useful reactions in which an a - and a d -synthon or two r -synthons are combined. The classical polar reaction is the addition of cyanide anion to carbonyl groups, which leads to a-hydroxynitriles (cyanohydrins). It is used, for example, in Strecker s synthesis of amino acids and in the homologization of monosaccharides. The ff-hydroxy group of a nitrile can be easily substituted by various nucleophiles, the nitrile can be solvolyzed or reduced. Therefore a large variety of terminal difunctional molecules with one additional carbon atom can be made. Equally versatile are a-methylsulfinyl ketones (H.G. Hauthal, 1971 T. Durst, 1979 O. DeLucchi, 1991), which are available from acid chlorides or esters and the dimsyl anion. Carbanions of these compounds can also be used for the synthesis of 1,4-dicarbonyl compounds (p. 65f.). 

An interesting variation of the cyanohydrin synthesis is based on the application of the Strecker reaction 118], or an appropriate modification of it, to protected dialdo sugars to give glycosyl a-aminonitriles, with good levels of diastereoselectivity (ds > 90%) [19]. This approach was employed for a formal synthesis of the amino octose lincosamine from... 

Similar to the cyanohydrin synthesis for hydroxy acids is the Strecker synthesis of amino acids. Aldehydes and ketones are converted to a-amino cyanides by ammonia and hydrogen cyanide or by aqueous ammonium chloride and sodium cyanide solutions. Amino cyanides may also be obtained by the action of gaseous ammonia on cyanohydrins (cf. method 391). The preparation of DL-alanine (60%) is typical. "... 

A modification of the cyanohydrin synthesis is provided by Strecker s amino acid synthesis, in which an <%-amino nitrile is obtained by the action of hydrogen cyanide and ammonia on an aldehyde or ketone ... 

STRECKER Ammoacidsynthesis Synthesis of a-amino acids from aldehydes or ketones via cyanohydrins... 

Miller (1953) demonstrated that the most plausible mechanism for the production of amino acids in his experiment was a Strecker or cyanohydrin synthesis. In later work it has become clear that parallel reaction pathways are possible, an addition of HCN to an aldehyde to produce the hydroxy-nitrile ... 

Inspired by the work of Inoue, Lipton and coworkers replaced the imidazole side chain of t icZo-peptide 50, which was efficient as catalyst in cyanohydrin synthesis from aldehydes (Scheme 13.29), with a more basic guanidine moiety in order to afford a catalyst capable of accelerating proton transfer in the Strecker reaction. The modified catalyst 52 was found to be effective in the synthesis of a-amino nitriles with very high yields from aromatic and aliphatic M-benzhydiyl imines, giving enantioselectivities of up to 99% (Scheme 13.30). ... 

Miscellaneous Reactions. Sodium bisulfite adds to acetaldehyde to form a white crystalline addition compound, insoluble in ethyl alcohol and ether. This bisulfite addition compound is frequendy used to isolate and purify acetaldehyde, which may be regenerated with dilute acid. Hydrocyanic acid adds to acetaldehyde in the presence of an alkaU catalyst to form cyanohydrin the cyanohydrin may also be prepared from sodium cyanide and the bisulfite addition compound. Acrylonittile [107-13-1] (qv) can be made from acetaldehyde and hydrocyanic acid by heating the cyanohydrin that is formed to 600—700°C (77). Alanine [302-72-7] can be prepared by the reaction of an ammonium salt and an alkaU metal cyanide with acetaldehyde this is a general method for the preparation of a-amino acids called the Strecker amino acids synthesis. Grignard reagents add readily to acetaldehyde, the final product being a secondary alcohol. Thioacetaldehyde [2765-04-0] is formed by reaction of acetaldehyde with hydrogen sulfide thioacetaldehyde polymerizes readily to the trimer. 

Hydroxyl Group. The OH group of cyanohydrins is subject to displacement with other electronegative groups. Cyanohydrins react with ammonia to yield amino nitriles. This is a step in the Strecker synthesis of amino acids. A one-step synthesis of a-amino acids involves treatment of cyanohydrins with ammonia and ammonium carbonate under pressure. Thus acetone cyanohydrin, when heated at 160°C with ammonia and ammonium carbonate for 6 h, gives a-aminoisobutyric acid [62-57-7] in 86% yield (7). Primary and secondary amines can also be used to displace the hydroxyl group to obtain A/-substituted and Ai,A/-disubstituted a-amino nitriles. The Strecker synthesis can also be appHed to aromatic ketones. Similarly, hydrazine reacts with two molecules of cyanohydrin to give the disubstituted hydrazine. 

Like the Strecker synthesis, the Ugi reaction also involves a nucleophilic addition to an imine as the crucial step in which the stereogenic center of an a-amino acid derivative is formed4. The Ugi reaction, also denoted as a four-component condensation (A), is related to the older Passerini reaction5 (B) in an analogous fashion as the Strecker synthesis is to cyanohydrin formation. In both the Ugi and the Passerini reaction, an isocyanide takes the role of cyanide. 

Remarks on Sections 6 and 7.-—The method here described for the synthesis of cyanohydrins—treatment of the bisulphite compound of the aldehyde with potassium cyanide—cannot be used in all cases. Concentrated solutions of hydrocyanic acid or anhydrous hydrogen cyanide are often used. The general method for the synthesis of a-amino-acids, the nitriles of which are formed by the union of ammonium cyanide with aldehydes or ketones (Strecker), is to be contrasted with that for the synthesis of a-hydroxy acids. For additional amino-acid syntheses see Chap. VII. 2, p. 276. 

The duration of the reaction time alone determines whether carbonyl compounds, sodium cyanide and ammonium chloride will generate a cyanohydrin (Figure 9.9, top) or an a-aminonitrile (Figure 9.9, bottom). We are already familiar with the first reaction pattern from the initial reaction of the three-step Kiliani-Fischer synthesis of aldoses (Figure 7.15). The second reaction pattern initiates the Strecker synthesis of a-amino acids, which is completed by a total hydrolysis of the C=N group, as in the Bucherer modification discussed elsewhere (Figure 7.11). 

The Strecker synthesis can form a large number of amino acids from appropriate aldehydes. The mechanism is shown next. First, the aldehyde reacts with ammonia to give an imine. The imine is a nitrogen analogue of a carbonyl group, and it is electrophilic when protonated. Attack of cyanide ion on the protonated imine gives the a-amino nitrile. This mechanism is similar to that for formation of a cyanohydrin (Section 18-14), except that in the Strecker synthesis cyanide ion attacks an imine rather than the aldehyde itself. 

The Strecker synthesis occurs by initial reaction of the aldehyde weth ammonia to give an imirte intermediate (Section Ld.9), which then adds HCX ir> a nucleof ilrc aridition step similar to what occurs in cyanohydrin formation (Section 16.7). The o amino nitrile that results undergnes hydml-ysts in the usual way (Section 21.SX... 

An amino nitrile may be formed instead of a cyanohydrin if the carbonyl compound is treated with aqueous ammonium chloride and sodium cyanide. Hydrolysis of the amino nitrile gives an a-amino acid as in the Strecker synthesis of r>L-alanine (Scheme 3.46). 

Mechanism 28.1 for the formation of the a-amino nitrile from an aldehyde (the first step in the Strecker synthesis) consists of two parts nucleophilic addition of NH3 to form an imine, followed by addition of cyanide to the C=N bond. Both parts are related to earlier mechanisms involving imines (Section 21.11) and cyanohydrins (Section 21.9). 

Strecker reactions are among the most efficient methods of synthesis of a-amino nitriles, useful intermediates in the synthesis of amino acids [73] and nitrogen-containing heterocycles such as thiadiazoles, imidazoles, etc. [74]. Although classical Strecker reactions have some limitations, use of trimethylsilyl cyanide (TMSCN) as a source of cyano anion provides promising and safer routes to these compounds [73b,75]. TMSCN is, however, readily hydrolyzed in the presence of water, and it is necessary to perform the reactions under strictly anhydrous conditions. BusSnCN [76], on the other hand, is stable in water and a potential source of cyano anion, and it has been found that Strecker-type reactions of aldehydes, amines, and BuaSnCN proceed smoothly in the presence of a catalytic amoimt of Sc(OTf)3 in water [77]. No surfactant was needed in this reaction. The reaction was assumed to proceed via imine formation and successive cyanation (it was confirmed that imine formation was much faster than cyanohydrin ether formation under these reaction conditions) again the dehydration process (imine formation) proceeded smoothly in water. 

The first total synthesis of amiclenomycin, an inhibitor of biotin biosynthesis, was completed by A. Marquet and co-workers. In order to prove its structure unambiguously, both the cis and trans isomers were prepared. The L-amino acid functionality was installed by a Strecker reaction using TMSCN in the presence of catalytic amounts of Znla. The resulting O-TMS protected cyanohydrin was exposed to saturated methanolic ammonia solution, which gave rise to the corresponding a-amino nitrile. Enzymatic hydrolysis with immobilized pronase afforded the desired L-amino acid. 

The conversion of cyanohydrins into a-amino nitriles is an analogous step in the Tiemann form of the Strecker synthesis and also takes place at or slightly above room temperature ... 

Strecker synthesis /strek-er/ A method of synthesizing amino acids. Hydrogen cyanide forms an addition product (cyanohydrin) with aldehydes ... 

Most of the elementary reactions in the classic MCRs are equilibrium processes. Therefore, thermodynamic factors can significantly impact the reaction pathways in addition to the reaction kinetics. A classic example is the Strecker synthesis of a-amino nitrile 9 from aldehydes, amines, and cyanide (Scheme 15.5). The key step in this reaction is the nucleophilic addition of cyanide to the in situ formed iminium. However, condensation of a carbonyl compound with an amine leading to iminium is an equilibrium process, especially under aqueous conditions. Therefore, the desired addition reaction is in competition with direct addition of cyanide to the aldehyde, leading to cyanohydrin 10. However, since the formation of both 9 and 10 were reversible, only the more stable adduct 9 was produced at the expense of cyanohydrin 10 under thermodynamically controlled conditions. 

Kinetic and Dynamic Resolution of rac-Nitriles. a-Hydroxy and a-amino acids can be obtained from the corresponding a-hydroxynitriles (cyanohydrins) and a-aminonitriles [684], which are easily synthesized in racemic form from the corresponding aldehyde precursors by addition of hydrogen cyanide or a Strecker synthesis, respectively (Schemes 2.107 and 2.108). In aqueous systems, cyanohydrins are stereochemically labile and undergo spontaneous racemization via HCN elimination, which furnishes a dynamic resolution process. From aliphatic rac-cyanohydrins, whole cells of Torulopsis Candida yielded the corresponding (S)-a-hydroxy acids [685], while (R)-mandelic add is produced from rac-mandelraiitrile... 

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